Compound for anti-cancer therapy that acts by targeting GOF mutant P53 and stimulates P73 to restore the P53 pathway signaling

Abstract

The invention includes compositions comprising NSC59984 or a derivative or analog thereof and a pharmaceutically acceptable carrier. The invention further includes methods of treating or preventing cancer in a subject, comprising the step of administering to the subject the compositions contemplated within the invention.

What is claimed is: 
     
       1. A method of treating colon cancer in a subject comprising administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (I) or a salt, solvate, or N-oxide thereof: 
       
         
           
           
               
               
           
         
         wherein in formula (I):
 ring A is a bicyclic aryl, a monocyclic or bicyclic heteroaryl, or a monocyclic or bicyclic heterocyclyl ring, and wherein the aryl, heteroaryl, or heterocyclyl ring is optionally substituted with 0-5 R 1  groups; 
 ring B is a monocyclic or bicyclic aryl, a monocyclic or bicyclic heteroaryl, or a monocyclic or bicyclic heterocyclyl ring, and wherein the aryl, heteroaryl, or heterocyclyl ring is optionally substituted with 0-5 R 2  groups; 
 the bond between carbon 1 and carbon 2 is either a single bond or a double bond; 
 each occurrence of R 1  and R 2  are independently selected from the group consisting of —C 1 -C 6  alkyl, —C 1 -C 6  fluoroalkyl, —C 1 -C 6  heteroalkyl, F, Cl, Br, I, —CN, —NO 2 , —OR 5 , —SR 5 , —S(═O)R 5 , —S(═O) 2 R 5 , —NHS(═O) 2 R 5 , —C(═O)R 5 , —OC(═O)R 5 , —CO 2 R 5 , —OCO 2 R 5 , —CH(R 5 ) 2 , —N(R 5 ) 2 —, —C(═O)N(R 5 ) 2 —, —OC(═O)N(R 5 ) 2 , —NHC(═O)NH(R 5 ), —NHC(═O)R 5 , —NHC(═O)OR 5 , —C(OH)(R 5 ) 2 , and —C(NH 2 )(R 5 ) 2 ; 
 R 3  and R 4  are each independently selected from the group consisting of H or C 1 -C 6  alkyl, wherein the alkyl group is optionally substituted with 0-5 R 1  groups; 
 each occurrence of R 5  is independently selected from the group consisting of H or C 1 -C 6  alkyl, wherein the alkyl group is optionally substituted; 
 x is an integer from 0 to 5; and 
 y is an integer from 0 to 5, 
 
         wherein the colon cancer is associated with a p53 gain of function (GOF) mutation. 
       
     
     
       2. The method of  claim 1 , wherein ring A is a monocyclic heterocyclyl ring. 
     
     
       3. The method of  claim 1 , wherein ring A is piperazinyl. 
     
     
       4. The method of  claim 1 , wherein ring A is 4-methyl piperazinyl. 
     
     
       5. The method of  claim 1 , wherein ring B is a monocyclic heteroaryl ring. 
     
     
       6. The method of  claim 1 , wherein ring B is a 5- or 6-membered heterocyclyl or heteroaryl ring. 
     
     
       7. The method of  claim 6 , wherein the heterocyclyl or heteroaryl ring has one heteroatom, wherein the heteroatom is alpha to the linkage between ring B and carbon 2. 
     
     
       8. The method of  claim 1 , wherein ring B is furyl. 
     
     
       9. The method of  claim 1 , wherein ring B is 5-nitrofuryl. 
     
     
       10. The method of  claim 1 , wherein R 3  and R 4  are each hydrogen. 
     
     
       11. The method of  claim 1 , wherein ring A has 1 to 2 ring heteroatoms. 
     
     
       12. The method of  claim 1 , wherein at least one of R 2  is selected from the group consisting of F, Cl, Br, I, —CN, —NO 2 , —C(═O)R 5 , —CO 2 R 5 , —S(═O)R 5 , and —S(═O) 2 R 5 . 
     
     
       13. The method of  claim 1 , wherein the bond between carbon 1 and carbon 2 is a double bond. 
     
     
       14. The method of  claim 1 , wherein the compound of formula (I) is (E)-1-(4-methylpiperazin-1-yl)-3-(5-nitrofuran-2-yl)prop-2-en-1-one (NSC59984) 
       
         
           
           
               
               
           
         
       
     
     
       15. The method of  claim 1 , further comprising administering another therapy to the subject. 
     
     
       16. The method of  claim 15 , wherein the other therapy is selected from the group consisting of radiation therapy, chemotherapy, and a combination thereof. 
     
     
       17. The method of  claim 16 , wherein the other therapy is administered to the subject at a lower level compared to the level when administered in the absence of the compound.